A class of ursolic acid derivatives containing pyrazole heterocycle and their synthesis and application

A technology of ursolic acid and synthetic method, which is applied in the direction of medical preparations containing active ingredients, drug combinations, steroids, etc.

Active Publication Date: 2019-08-27
SHANGHAI ADVANCED RES INST CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chemotherapy drugs used clinically at this stage mostly play a killing role by causing tumor cell apoptosis, but the delay of chemotherapy time will lead to the formation of tumor drug resistance

Method used

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  • A class of ursolic acid derivatives containing pyrazole heterocycle and their synthesis and application
  • A class of ursolic acid derivatives containing pyrazole heterocycle and their synthesis and application
  • A class of ursolic acid derivatives containing pyrazole heterocycle and their synthesis and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Dissolve 460mg of ursolic acid (1) and 280mg of anhydrous potassium carbonate in 10ml of N,N-dimethylamide, then add 300mg of BnBr, and heat the reaction mixture at about 60°C for 4 hours until the reaction is complete. The mixture was cooled to room temperature, and 50 mL of H 2 O, a white solid was precipitated. The obtained solid was successively filtered, washed with water, and vacuum-dried to obtain 0.50 g of intermediate (2), and the yield of intermediate (2) was 92%.

[0101] The spectrum identification result of intermediate (2) is as follows:

[0102] 1 H NMR (500MHz, CDCl 3 ):δ=7.36-7.29(m,5H),5.24-5.23(m,1H),5.10(d,J=12.5Hz,1H),4.98(d,J=12.5Hz,1H),3.20(dd, J=11.0,4.5Hz,1H),2.04-1.98(m,1H),1.89-1.76(m,3H),1.73-1.67(m,2H),1.64-1.55(m,4H),1.53-1.44( m,6H),1.37-1.26(m,6H),1.07(s,3H),1.05-1.02(m,2H),0.98(s,3H),0.93(d,J=6.0Hz,3H),0.89 (s,3H),0.85(d,J=6.5Hz,3H),0.78(s,3H),0.64(s,3H).

[0103] 13 C NMR (125MHz, CDCl 3 ):δ=177.3,138.1,136.3,128.4(2C),128.1(2C...

Embodiment 2

[0107] Dissolve 450 mg of intermediate (2) in 50 mL of anhydrous dichloromethane, cool to below 0°C, add 355 mg of PCC for reaction, and slowly warm the mixture to room temperature and stir for about 12 hours until the reaction is complete. The reaction mixture was filtered through diatomaceous earth to remove insoluble matter, the organic phase was concentrated under pressure, and the residue was separated and purified by silica gel column chromatography to obtain 375 mg of intermediate (3). Intermediate (3) was a white solid. The yield was 84%.

[0108] The spectrum identification result of intermediate (3) is as follows:

[0109] 1 H NMR (500MHz, CDCl 3 ):δ=7.37-7.29(m,5H),5.25(t,J=3.5Hz,1H),5.11(d,J=12.5Hz,1H),4.99(d,J=12.5Hz,1H),2.57 -2.50(m,1H),2.40-2.34(m,1H),2.27(d,J=11.5Hz,1H),2.04-1.98(m,1H),1.92-1.87(m,3H),1.82-1.68 (m,3H),1.64-1.54(m,3H),1.50-1.41(m,5H),1.35-1.28(m,4H),1.10-1.07(m,1H),1.08(s,6H),1.03 (d,J=9.0Hz,6H),0.93(d,J=6.0Hz,3H),0.85(d,J=6.5Hz,3H),0.68(s,...

Embodiment 3

[0114] 300 mg of intermediate (3) was dissolved in 20 mL of anhydrous tetrahydrofuran, the reaction solution was cooled to 0°C, 45 mg of sodium methoxide was added thereto, and then 45 mg of ethyl formate was added. The reaction mixture was stirred at room temperature for about 4 hours until the reaction was complete. A small amount of water was added to quench the reaction and the mixture was extracted three times with ethyl acetate (3x30ml). The combined organic phases were sequentially washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated, and the residue was quickly separated by silica gel column chromatography to obtain intermediate (4a).

[0115] The spectrum identification results of intermediate (4a) are as follows:

[0116] 1 H NMR (500MHz, CDCl 3 ): δ=14.92(br s,1H), 8.57(s,1H), 7.37-7.30(m,5H), 5.28(t,J=3.3Hz,1H), 5.12(d,J=12.5Hz,1H ),4.99(d,J=12.5,1H),2.32-2.28(m,2H),2.05-1.92(m,4H),1.82-1.69(m,3H),1...

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Abstract

The invention provides a general structural formula of an ursolic acid derivative containing a parazole heterocycle. The invention further provides a synthetic route of the ursolic acid derivative containing the parazole heterocycle and synthesis steps of the ursolic acid containing the parazole heterocycle. The invention also provides application of the ursolic acid derivative containing the parazole heterocycle in preparation of a drug used for treating tumor. The ursolic acid derivative as well as synthesis and application thereof, which are provided by the invention, have the advantages that in vitro anti-tumor activity tests show that the compound has obvious inhibiting effect on tumor growth, provides a new target spot and a new treatment strategy for development of anti-tumor drugs and has potential of being developed into a novel anti-tumor drug.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy and relates to a class of ursolic acid derivatives containing a pyrazole heterocycle and their synthesis and application, in particular to a class of ursolic acid derivatives containing a pyrazole heterocycle and a synthesis method thereof and are used in the treatment of Application of tumor drugs. Background technique [0002] Tumor is one of the most serious diseases that endanger human health at present, and the incidence of tumor is increasing year by year worldwide. In China, the annual mortality rate of cancer remains high. The occurrence and development of tumor is a complex multi-factor and multi-stage process. Its occurrence and development are closely related to the abnormal expression of related genes regulating cell proliferation and death. There are mutations of tumor suppressor genes in tumor cells, which reduce the sensitivity of tumor cells to apoptosis. At the same ...

Claims

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Application Information

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IPC IPC(8): C07J71/00A61K31/58A61P35/00
Inventor 苏小惠李斌孙琳魏万国
Owner SHANGHAI ADVANCED RES INST CHINESE ACADEMY OF SCI
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